The development of a new drug candidate for the treatment of Pneumocystis carinii pneumonia and azole-resistant Candida albicans, and the identification of one or more potential new therapeutic targets in these OI pathogens is proposed. Pseudolaric Acid B (PLAB), a diterpene acid isolated from the bark of a Chinese medicinal plant, Pseudolarix kaempferi, is proposed as a lead compound for the development of a new class of antipneumocystic and antifungal agents. PLAB appears to exert its antifungal activity and antipneumocystic activity by a novel mechanism of action involving a previously unrecognized therapeutic molecular target in these AIDS-related OI pathogens. To accomplish the objectives of new drug development and validation of the proposed new therapeutic target(s), pharmacophore-based tools for drug design by synthesis and bioassay are proposed. Parallel mechanisms of action studies are also proposed. Specifically, these goals will be met by completing ongoing studies directed towards the total synthesis of PLAB using methods that will also provide for construction of analogs not available by semi-synthesis (including carbon-14 labeled PLAB for use in mechanism of action studies); by preparing through semi-synthesis, PLAB analogs from PLAB and PLAC, both of which are in the process of being isolated from bulk quantities of Pseudolarix amabilis; by evaluating all prepared PLAB analogs for in vitro and in vivo inhibition of P. carinii and other fungal OI pathogens and for inhibition/activation of specific molecular targets; by determining the mechanism of action of PLAB and its active analogs by correlating effects on specific molecular targets with whole cell inhibitory effects; and, utilizing data derived above to design mechanism-based inhibitors/ activators of a specific therapeutic target.
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